Among potential changes is that manufacturers will have to anticipate customers’ intended use of their IVD products.

FDA has found that products for research-use or investigational-use only have been leveraged in the clinic. [Stefan Rajewski - Fotolia.com]

The FDA can expect an earful from groups representing diagnostic makers and clinical molecular lab professionals over the draft guidance it released concerning the labeling of in vitro diagnostic (IVD) products marked “for research use only” (RUO) and “for investigational use only” (IUO).

The agency hopes to stop companies from getting around its medical device review process for the commercialization of diagnostics. IVD products used in lab research are exempt from most of the regulatory requirements that apply to IVD medical devices for public consumption, including premarket approval, premarket notification, and good manufacturing practice requirements.

“We have noted an increase in products being marketed in ways that suggest they have clinical use, even though the products are labeled for research use only,” Elizabeth Mansfield, Ph.D., the FDA’s director for personalized medicine in the Office of In Vitro Diagnostics in the Center for Devices, told GEN. “We are concerned that these products, which generally are manufactured without important controls, and for which there is no reporting of adverse events, are being widely used for clinical diagnostic applications.”

Dr. Mansfield said the FDA has sent “a small number of letters” to undisclosed manufacturers that have misused their RUO or IUO product labels: “We believe there is some misuse of these labels and are supplying guidance on appropriate labeling.”

In interviews with GEN, groups representing molecular diagnostic developers and molecular pathologists expressed separate yet similar concerns that the draft guidance could lead to regulations that disrupt the operations of clinical molecular labs. By extension, they argue, the guidance could also disrupt the very process of developing new drugs.

Clinical Lab Impact

“Even though this has clearly been targeted to manufacturers of RUO and IUO products, it will have an impact on clinical laboratories and clinical laboratory operations,” David Mongillo, vp for policy and medical affairs with the American Clinical Laboratory Association (ACLA), told GEN. “In some cases, the only technologies and reagents available for very important clinical services are RUO/IUO. And if they weren’t available, it would have an impact on physicians ordering these tests and their patients.”

ACLA, which lists 45 members on its website, most of them diagnostics developers, is among groups that plan to submit feedback to the FDA during the 90-day comment period the agency has launched on its draft guidance titled “Commercially Distributed In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only: Frequently Asked Questions.” The guidelines were released on June 1, and the deadline for comments is August 30.

Also planning to submit comments are the American Society of Hematologists, a professional society whose 15,705 members focus on the causes and treatment of blood disorders; and the Association for Molecular Pathology (AMP), which specializes in clinical molecular laboratory medicine and translational research based on molecular biology, genetics, and genomics

“The advent of ASRs (analyte-specific reagents) enabled laboratories to use commercial products for patient benefit that would otherwise not be available. However, some products necessary for laboratory tests are available only as RUOs. The FDA RUO guidance may affect availability of certain tests, which, in turn, may limit a healthcare provider’s ability to manage patient care,” Mary Steele Williams, AMP’s COO and director of scientific programs, told GEN.

Dr. Mansfield said it was unlikely the draft guidance would delay drug development, noting that it applies to devices and was written with the purpose of informing manufacturers how they should market RUO- and IUO-labeled products. “We do not intend to interrupt laboratory testing, but we hope that laboratories will encourage their suppliers to conform with regulations as soon as possible,” Dr. Mansfield remarked.

Also unlikely, she said, were clinical trial delays due to concerns about relabeling RUO and IUO products: “Most products will not require relabeling for use in clinical trials. The appropriate labeling for products in the clinical trial phase is ‘for investigational use,’ and this type of labeling typically requires only compliance with the investigational regulations.”

New Definitions

The draft guidance defines two categories of RUO products, each with the label: “For Research Use Only. Not for use in diagnostic procedures.’’ One category is products in the laboratory research phase of development that are intended to assist with the development of a commercial IVD product, which include:

tests that are in development to identify test kit methodology, necessary components, and analytes to be measured;

instrumentation or other electrical/mechanical components under development to determine correct settings, subcomponents, subassemblies, basic operational characteristics, and possible use methods; and

reagents under development to determine production methods, purification levels, packaging needs, shelf and storage life, etc.

The other RUO category includes products intended for nonclinical lab research, such as those for use in discovering and developing basic medical knowledge of human disease and conditions. Among examples are instruments and reagents that are being leveraged in research attempting to isolate a gene linked with a particular disease.

IUO products are those that are being shipped or delivered for product testing prior to full commercial marketing. The guidance gives as an example products developed for use on specimens derived from humans to compare the usefulness of the product with other products or procedures that are currently in use or recognized as useful. The label of an IUO must read, “For Investigational Use Only. The performance characteristics of this product have not been established.’’

According to the FDA, RUO and IUO products may also be marketed for and used in the research and investigation of other products. Thus, a manufacturer who labels its IVD product RUO may promote and market it for research use, for example, by general discovery laboratories. By the same token, a manufacturer who labels its IVD product IUO may promote and market it for use in a clinical investigation that is exempt from federal regulations covering investigational device exemptions.

Shifting Responsibility

In perhaps the biggest departure from current practice, the draft guidance directs that as a manufacturer knows “or has reason to know” that laboratory customers are using an RUO or IUO in vitro diagnostic product for a clinical diagnostic or patient-management purpose, it should stop selling the product to those customers.

In addition to judging marketing activities by assessing overt claims or expressions by manufacturers as can be found on their labels and in their ads, FDA will also consider the use intended by manufacturers for RUO- and IUO-labeled products based on “the circumstances surrounding the distribution of the product and the manufacturer’s knowledge that its product is offered and used for a purpose for which it is neither labeled nor advertised.

“For example, FDA may consider a manufacturer’s knowledge of the purposes for which its customers offer and use its IVD product and the manufacturer’s provision of technical support for those activities to be evidence that the IVD product is intended to be used for such purposes. The weight of this evidence will vary with the circumstances,” the draft guidance states.

Now, manufacturers can avoid a run-in with the FDA over their marketing of RUO and IUO products if they agree to obtain clearance or approval for the test in question. In doing so, though, they will invite even more attention from the agency. This change has the potential to be felt beyond the regulation of RUO and IUO products, since it puts manufacturers in the position of having to guess the intent of their customers or risk getting in trouble with the FDA.

Significantly neither FDA, industry groups, nor any other entity has an educated guess on how prevalent the use of RUO and IUO products is within laboratory developed tests (LDTs). The guidance covering RUO and IUO products could also be another hurdle for the direct-to-consumer (DTC) genetic testing industry, which FDA has also scrutinized in recent months. As with LDTs, nobody has a handle on how many DTC tests use RUO and IUO components. Anecdotal examples have emerged over the past year, though; Illumina’s Omni family of microarrays, for one, carries an RUO label.

As with manufacturers of diagnostics, technology companies like Illumina may be forced to choose between using RUO and IUO components, risking the wrath of the FDA going forward; subjecting their products automatically to the agency’s medical review process; or avoiding the use of their products by direct-to-consumer testing companies altogether.

So in cracking down on RUOs and IUOs, FDA’s draft guidance creates rules that could affect more than just LDTs and DTCs. Both industries can be expected to argue that those rules are anything but A-OK.